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33
both MUGA and cardiac CT incorporate ionizing
radiation—a limitation in those who may have
additional ionizing radiation exposure for cancer
treatment with external beam radiation therapy
[46]. Thus, imaging modalities such as echocar-
diography or CMR are preferred to reduce expo-
sure to ionizing radiation.
The diagnostic utility of LVEF in monitoring
cardio-oncology patients has limitations, however,
as many key therapies induce cardiotoxicity, which
may manifest in other adverse injuries and events
prior to a change in LVEF.These co- morbidities
include valvular and pericardial disease, myocel-
lular injury, diastolic dysfunction, and vascular
injury. Patients with high grades of cardiotoxicity
on biopsy can have normal LVEF measures [47]
and a growing body of work demonstrates that dia-
stolic dysfunction and heart failure may precede
asymptomatic LVEF depression [39]. While cur-
rent noninvasive surveillance techniques are accu-
rate at detecting changes in LVEF they miss the
opportunity to detect the early, reversible manifes-
tations of myocardial injury after receipt of ther-
apy for cancer [48]. Comprehensive examinations
with imaging modalities should include not only
LVEF evaluations but also other markers of sys-
tolic and diastolic function.
Left Ventricular Strain
A hallmark of left ventricular dysfunction in
echocardiography, myocardial strain, may be
measured with either 2D or 3D speckle tracking
echocardiography or tissue Doppler imaging [37,
49]. Global longitudinal strain increases acutely
just 1 week after anthracycline treatment from
−17.8 ± 2.1 to −16.3 ± 2.0 (p < 0.01) before
detectable changes in LVEF [50]. Diminished
global longitudinal and radial strain measures
have also been observed 3months after anthracy-
cline and trastuzumab treatment for breast cancer,
which forecasted reductions in LVEF at 6months
[34, 51]. An early reduction of 10–15% in global
longitudinal strain is predictive of LVEF decline
or heart failure [52]. Changes in echocardio-
graphic measures of diastolic function including,
decreased E/A ratio, prolonged isovolumic relax-
ation time, and prolonged deceleration time for
early diastolic lling have been reported [53–56];
these changes, however, appear transient and
their association with long term LVEF reduction
remains unclear.
Serial measures of myocardial strain may also
be accomplished with CMR imaging by either
spatial modulation of magnetization or displace-
ment encoding with stimulated echo CMR to
measure the Eulerian circumferential strain [57,
58], however, limited data exist for serial CMR
strain measures in cardio-oncology patients.
Notably, however, in a prospective study of 53
individuals treated for breast cancer or hemato-
logic malignancies with low to moderate doses of
anthracyclines, circumferential strain (loss of
contractility) signicantly increased during a
period of subclinical decline in LVEF within
1–6months following initiation of treatment [59].
Future studies are needed to determine prognostic
value of abnormal myocardial strain by CMR in
cardio-oncology patients. It is important to note
that myocardial strain measures (longitudinal,
radial, or circumferential) can be affected by both
time dependent increases in LV end-systolic vol-
ume or decreases in LV end- diastolic volume.
Cancer patients undergoing therapy can experi-
ence a decrease in appetite, nausea, vomiting, or
diarrhea that reduce left ventricular preload and
promote decrements in LVEF and myocardial
strain [60]. Therefore, when assessing myocardial
strain, simultaneous assessments of LV volumes
should also be performed so that strain changes
may be interpreted while simultaneously consid-
ering LV volumes [61, 62].
Evaluation of cardiovascular dysfunction by
markers of LV volumes, LVEF, and strain may be
performed with a variety of imaging modalities
with increasingly high reproducibility and accu-
racy, however, these imaging parameters are
unable to distinguish the underlying cause of
dysfunction. Cardiovascular magnetic resonance
with tissue characterization techniques such as
T1 mapping may be able to dene the etiology of
cardiovascular dysfunction in cardio-oncology
patients at risk for cardiovascular events.
3 T1 Mapping inCardiomyopathy fromCancer Treatment
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T1 Mapping inCardio-oncology
T1 mapping reects intra- and extra-cellular
myopathy including inammation, edema, and
brosis (see Chap. 1) that are included in the
spectrum of cardiotoxicity from cancer treat-
ments. This section reviews the historical evi-
dence of T1 changes in cardiomyopathy from
cancer treatment through evolving imaging meth-
odologies and application to the eld to identify
myocardial injury and brosis through semi-
quantitative and quantitative methods.
Myocardial Injury
While current noninvasive surveillance tech-
niques are accurate at detecting changes in LVEF,
they miss the opportunity to detect the early,
reversible manifestations of myocardial injury
after receipt of doxorubicin [48, 63]. Studies
from the 1970s demonstrated that intracellular
and extracellular myocardial edema are early
manifestations of cardiac injury that occur before
myocellular death, increased collagen deposi-
tion, reduced contractile performance, and left
ventricular remodeling [64, 65]. Spectroscopy
and nuclear magnetic resonance used in rodent
studies of cardiotoxicity demonstrated an
increase in myocardial T1 of rodents with histo-
logical evidence of myocardial injury and cardio-
toxicity [66, 67].
Following these spectroscopic observations
of T1 changes, several semi-quantitative
T1-weighted CMR studies using early and late
gadolinium enhancement were performed. In
clinically stable patients treated with anthracy-
clines and imaged serially with early enhance-
ment T1-weighted CMR, a relative enhancement
>5 on day 3 predicted a signicant decline in
LVEF at day 28 [68]. Similarly, mean signal
intensity of the myocardium on late gadolinium
enhancement images predicted declines in LVEF
in a rodent model of doxorubicin cardiotoxicity
[69]. As demonstrated in the histopathology in
Fig. 3.5, the increase in mean late gadolinium
enhancement T1-weighted signal intensity of
doxorubicin-treated animals with LVEF drops
was associated with vacuolization. These early
serial changes in late gadolinium enhancement
T1-weighted signal intensity were then replicated
in a clinical population as early as 3months after
initiation of chemotherapy [70]. Following these
and other studies, newer quantitative mapping
techniques became available to resolve limita-
tions of T1-weighted imaging that identied
myocardial changes but could not discriminate
well between acute injury and myocardial bro-
sis and were difcult to perform in multi-center
clinical designs due to scanner variability.
Myocardial Fibrosis
Though published quantitative T1 mapping data
in the eld of cardio-oncology is limited, the util-
ity of noninvasive tissue characterization in this
population with complex, heterogeneous under-
lying risk factors for extracellular and intracellu-
lar pathologies is promising particularly given
the myriad of cardiovascular consequences of
therapies (Table3.2). Studies have identied the
correlation of collagen volume fraction with
CMR measures of extracellular volume (see
Chap. 1) and the ability to perform T1 mapping
with and without contrast discriminates between
intra- and extra-cellular processes. Cancer treat-
ments may involve complex treatments such as
radiation therapy followed by anthracycline che-
motherapy, each with independent risk of devel-
oping myocardial brosis (Fig. 3.6). Thus, T1
and ECV mapping with CMR offers the ability to
noninvasively perform serial assessments of the
myocardial substrate, particularly in those at high
risk or with underlying cardiovascular comor-
bidities that may contribute to baseline increases
in extracellular volume. Myocardial brosis may
be the new frontier in cardiotoxicity and thus,
CMR with T1 and ECV is well poised for appli-
cation in this population [10].
In a cross-sectional study of symptomatic
adult survivors treated with anthracycline chemo-
therapy who later underwent clinically indicated
3T CMR examinations (89±40 months), ECV
J. H. Jordan and W. G. Hundley
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35
was elevated compared to healthy controls
(36 ± 3%, p < 0.0001) [71]. Furthermore, the
ECV was highest among survivors with reduced
LVEF compared to survivors with preserved
LVEF (38±3% vs. 36±2%, p=0.03), suggest-
ing that there may be a stepwise progression of
ECV with respect to LVEF reduction and
increased ECV and myocardial brosis may pre-
cede LVEF reductions (Fig.3.7). In pediatric sur-
vivor populations 7–10years after treatment with
anthracyclines, T1 and ECV have measured in
the normal range in aggregate, however, a small
proportion of asymptomatic subjects exhibited
Serial histograms and histopathology.
Normal Saline
2
# Pixels
Intensity
Intensity
Longitudinal Section: H and E 40x
# Pixels
# Pixels
03
4
DOX: No EF Drop
DOX: EF Drop
Histogram: Intensity at 4 weeks
8
6
4
2
0
8
6
4
2
0
8
6
4
2
0
-100 100 2000
-100 100 2000
Intensity
-100 100 2000
Fig. 3.5 Serial histograms and histopathology of changes
in myocardial tissue following administration of chemo-
therapy with qualitative CMR imaging. Four week histo-
grams of the number of pixels (y axes) and intensities (x
axes) in individual animals after receipt of normal saline
(top left), doxorubicin (DOX) without an EF drop (top
middle), and DOX with an EF drop (top right). Increases
in signal intensity represent contrast enhancement in areas
of myopathy. The bottom row displays 40× hematoxylin
and eosin histopathologic images from the same animals.
The increased mean intensity in the animals with an LVEF
drop corresponds with vacuolization (arrows, bottom
right) and increased extracellular volume (dashed arrows,
bottom right) on histologic images. Reprinted with per-
mission from [
69]
Table 3.2 Cardiac lesions associated with cancer
therapies
Interstitial Myocellular
Intramyocardial
vascular
Diffuse
interstitial
brosis
Reparative
brosis
Perivascular
brosis
Myobrillar loss
Vacuolizations
Necrosis
Apoptosis
Chromatin
condensation
Picknotic nuceli
Vessel
thickening
Endothelial
injury
Perivascular
brosis
This table lists cardiac lesions that may occur after cancer
therapy administration categorized by location, many of
which may contribute to changes in T1 values in cancer
patients
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36
elevated ECV similar to adult survivors (38±7%)
[72, 73]. Interestingly, increased ECV correlated
with increased cumulative dose of anthracy-
clines, reduced exercise capacity (peak VO2),
and LV remodeling measures (Fig.3.8).
More recent ndings using T1 mapping in
the cardio-oncology setting have shown that
T1 and ECV are elevated in anthracycline-
treated cancer survivors earlier (2years after
treatment) and elevations in T1 and ECV are
independent of other factors that may contrib-
ute to myocardial brosis including age, gen-
der, cardiovascular risk factors, and LV
remodeling parameters (Fig.
3.9) [74]. These
study results demonstrate the incremental
effect of anthracyclines on development of
myocardial brosis that can be identied non-
invasively with T1 mapping (Fig. 3.10).
Moreover, anthracycline-induced myocardial
brosis has been observed in serial imaging as
early as 3months after initiation of chemother-
apy (Fig.
3.11) [75], suggesting the need for
potential early surveillance using T1 mapping
within CMR protocols as shown in Table 3.3
for assessment of left ventricular function and
tissue characterization in cardio-oncology
patients. In a recent animal model, early edema
and brosis were strongly associated with and
was predictive of late mortality [76]; these
ndings, however, have not been replicated yet
in a longitudinal clinical study. Several studies
addressing the NIH cardiotoxicity workshop
recommendations are actively investigating the
development of myocardial brosis and its
relationship with late outcomes including, LV
dysfunction, fatigue, and reduced exercise
capacity previously observed in cardio-oncol-
ogy populations [77].
0.50
#
¶
0.45
0.40
0.35
0.30
0.25
0.20
CTRL
Extracellular Volume Fraction
AC-ALL AC-PEF AC-REF
Fig. 3.7 Extracellular volume fraction is elevated in
anthracycline-treated cancer survivors. Aggregate mean
and ranges of myocardial ECV in healthy controls (CTRL)
and patients with previous anthracycline treatment
(AC-ALL). Survivors (AC-ALL) were then divided into
with preserved LVEF (AC-PEF) and those with reduced
LVEF (AC-REF). ECV was elevated in AC-ALL com-
pared to healthy CTRL participants (#p < 0.001).
Furthermore, ECV was higher in those with reduced LVEF
(AC-REF) than those with preserved LVEF (AC-PEF)
(¶p=0.03). Reprinted with permission from [71]
abc
Fig. 3.6 Case example of diffuse myocardial brosis
with T1 mapping and elevated ECV in cancer survivor. A
40year old female treated 14years prior with whole body
radiation and three courses of high dose anthracycline-
based chemotherapy. The patient had LV systolic dysfunc-
tion (LVEF 39%) with no evidence of late gadolinium
enhancement using CMR imaging. As shown in (a), the
Native T1 was homogenously elevated (>1000 ms) and
both septal and right ventricular extracellular volume
were also elevated at 38% and 45%, respectively (b).
Tissue histology after heart transplantation for intractable
right heart failure revealed extensive ne interstitial bro-
sis (black arrows) around myocytes (white arrows) by
Masson’s trichome stain (c). Images courtesy Matthias
Schmitt, MD, PhD (North West Heart Centre, University
Hospital of South Manchester)
J. H. Jordan and W. G. Hundley
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37
400.0 70.0
60.0
50.0
40.0
30.0
20.0
15.0 20.0 25.0
300.0
r = 0.40
p = 0.036
r = -0.52
p = 0.005
200.0
100.0
0.0
15.0 20.0
Extra Cellular Volume Fraction (ECV, %)
Extra Cellular Volume Fraction (ECV, %)
25.0
Anthracycline Dose (mg/m
2
)
Peak VO
2
(ml/kg/min)
ab
Fig. 3.8 Elevations in ECV of pediatric survivors treated
with anthracycline chemotherapy correlates with markers
of cardiovascular dysfunction and heart failure.
Correlation of extracellular volume fraction (ECV) with
(a) anthracycline dose, (b) peak VO2, (c) left ventricular
mass/LVEDV and (d) LV wall thickness/height in 30
asymptomatic pediatric cancer survivors treated with
anthracycline chemotherapy 7.6±4.5years prior to ECV
imaging. Reprinted with permission under Open Access
from [72]
r = -0.64
p < 0.001
r = -0.72
p < 0.001
0.90 0.50
0.45
0.40
0.35
0.30
0.25
0.80
0.70
0.60
0.50
0.40
LV Mass/LVEDV (g/ml)
LV Wall Thickness / Height (cm/m)
15.0 20.0
Extra Cellular Volume Fraction (ECV, %)
25.0
15.0 20.0
Extra Cellular Volume Fraction (ECV, %)
25.0
cd
New Challenges inT1 Mapping
inCardio-oncology
Challenges and limitations still remain in the
application of T1 mapping to assess cardiomy-
opathy from cancer therapy. There is a growing
concern in the use of gadolinium-based contrast
agents, particularly in those who receive serial
contrast exams [78–80]. This may limit the utility
of contrast T1 and ECV mapping in this
population for serial surveillance. Emerging
non- contrast techniques and variants of T1 map-
ping, such as T1-rho mapping [81–83] and mag-
netization transfer mapping, should be evaluated
in this population and considered for use in those
unable to receive gadolinium contrast for ECV
and brosis quantication. Furthermore, there is
now increasing evidence of both early myocar-
dial brosis and acute injury in cancer patients;
however, reliable discrimination of these disease
entities continues to be difcult but presents
opportunities for recovery as presented in
Fig.3.12 [10, 74, 84]. Delineation of the complex
cardiovascular pathologies that occur after can-
cer treatment (Table 3.2) could be aided by T2
mapping or the use of biomarkers.
3 T1 Mapping inCardiomyopathy fromCancer Treatment
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38
50
p < 0.0001
p = 0.19
p < 0.01
40
30
20
26.9
Control
Age-adjusted values expressed as
Pre-Treatment Post-T
reatment
27.8
n=196 n=27 n=24
30.4
10
0
Myocardial ECV (%)
µ ± σ
Fig. 3.10 Aggregate data of myocardial ECV demonstrat-
ing elevated ECV in cancer survivors. Myocardial extracel-
lular volume (ECV) assessments of 2-year post- anthracycline
cancer patients (right, red triangle) are elevated compared to
newly diagnosed cancer patients yet to begin treatment
(middle, blue circle) and cancer-free comparators from the
Multi-Ethnic Study of Atherosclerosis (left, green diamond).
ECV incrementally increases across each group
(p<0.0001). Reprinted with permission from [74]
A
34
p=0.001 p=0.003
Baseline
3 Months
32
30
28
26
24
LV LV Septum
Extracellular Volume (%)
Fig. 3.11 Increases in myocardial brosis measured with
CMR ECV may occur as early as 3months after receipt of
chemotherapy. Extracellular volume (ECV) analysis dis-
playing the mean±standard deviations before (blue) and
3months after (red) initiation of chemotherapy. ECV was
evaluated in the entire LV short axis (average of all
accepted segments, solid bars) and in the LV septum
(striped bars). Image courtesy Giselle C.Meléndez, MD
(Wake Forest School of Medicine, Winston-Salem, North
Carolina)
No Cancer
ECV = 27%
ECV (%)
ECV = 25% ECV = 32%
Cancer
Pre-Treatment
Cancer
Post-Treatment
62 year old man with
hypercholesterolemia
66 year old woman
with hypertension and
hypercholesterolemia
63 year old woman
with hypertension
Fig. 3.9 Case examples of ECV maps demonstrating
elevated ECV in a cancer survivor treated with anthracy-
cline. Representative ECV maps from three participants
of similar age and comorbidity burden either without can-
cer (left), newly diagnosed cancer yet to receive treatment
(middle), and 2years after cancer treatment (right) exhib-
iting diffuse increases in elevated extracellular volume of
the cancer survivor. Reprinted with permission from [74]
J. H. Jordan and W. G. Hundley
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Table 3.3 CMR Protocol for assessment of cardiomyopathy and cancer treatment effects in cancer patients
Scan Assessment
Localizers Extra-cardiac abnormalities including metastases and
aortic stenosis/enlargement
Long axis (LAX) cines(2, 3, 4 Chamber) Myocardial contractility
Wall motion abnormalities
Global longitudinal strain
Short axis (SAX) cines LV volumes and mass
Wall motion abnormalities
Circumferential strain
Native T1 mapping(3 SAX + 3 LAX views) Inammation
Edema
Fibrosis
T2 mapping(3 SAX + 3 LAX views) Inammation
Edema
Tagging
(3 SAX + 3 LAX views)
Global longitudinal strain
Circumferential strain
If eligible, administer Gadolinium (Gd) contrast agent
Post-Gd T1 mapping(3 SAX + 3 LAX views) Fibrosis
TI scout Inversion time determination
Late gadolinium enhancement(SAX stack + 3 LAX
views)
Fibrosis
Microvascular obstruction
This table demonstrates the scans in a suggested CMR protocol for the cardio-oncology patient. If possible, gadolinium
contrasted scans provide additive value in describing the etiology of cardiovascular dysfunction
Normal cardiomyocytes
Normal cardiomyocytes
Cardiomyocyte death
Cardiomyocyte dysfunction
Cumulative doxorubicin
Dead cardiomyocytes
Cardiomyocytes with mitochondrial dysfunction
Atrophied cardiomyocytes with decreased myofibrils
Affected area
Compensation
Remodeling of
unaffected area
Remodeling of
unaffected area
Attenuation of functional
abnormalities
Fig. 3.12 Potential mechanisms for recovery from
doxorubicin- induced cardiomyopathy. Cardiotoxicity is
complex, multifactorial process that includes both irre-
versible cardiomyocyte death and potentially reversible
dysfunction (e.g., mitochondrial defects, atrophy, and
myobrillar loss). Interventions aimed at attenuating dys-
function or compensating with the uninvolved myocar-
dium may present opportunities for mitigating cardiotoxic
effects in the myocardium. Reprinted with permission
from [84]
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Summary
To date, the vast majority of cardio-oncology
research has focused on myocellular injury and
LV dysfunction. Current surveillance strategies
focused only on LVEF after symptoms may miss
the onset of subclinical brosis and other early
pathophysiologic manifestations, which require
different therapy to prevent myocellular injury.
Early work, utilizing T1 and ECV mapping in
cardio-oncologic clinical studies, serves as a
foundation for additional research to investigate
the onset of myocardial brosis and its relation to
cardiovascular mortality and exercise intolerance
observed in cancer survivors. New clinical path-
ways are necessary to detect this early disease
process to improve the cardiovascular health of
cancer survivors.
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